Introduction Neurodegenerative diseases were associated with a decrease in histone acetylase transferase (HAT) activity, resulting in relative over-deacetylation. Histone deacetylase (HDAC) inhibitors were suggested as potentially neuroprotective agents. The aim of this sudy was to evaluate the neuroprotective effects of valproic acid (VPA), an histone deacetylase inhibitor, in beonatal hypoxic ischemic rat model.
Methods After being anesthetized, 7-day-old pups underwent ischemia followed by exposure to hypoxia. The pups were divided into 3 groups: sham group, vehicle group (saline group) and VPA group. VPA was administered intraperitoneally for three times; the first just after hypoxia-ischemia, the second and the third doses 24 and 48 hours after the first dose, respectively. After sacrification; brain infarct volume, apoptosis, HDAC activity, acetylated H4 protein and caspase 3 expression, and proinflammatory cytokine concentrations were evaluated in brain tissue of rat pups.
Results Percent infarcted brain volume and number of TUNEL positive cells per unit area in hippocampus and cortex CA1 were markedly reduced with VPA treatment. HDAC activity was found to be significantly reduced in VPA group, whereas acetylated H4 protein expression was significantly increased with VPA treatment. The caspase-3 activity in VPA group was significantly lower than the control group. The roinflammatory cytokine levels also significantly decreased with VPA treatment.
Conclusion This is the first study that showed the neuroprotective effects of VPA treatment as an HDAC inhibitor by reducing percent infarcted brain volume, histone deacetylase activity, inflammation and apopotosis while increasing acetylated H4 protein levels in a neonatal hypoxic-ischemic rat model.
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